Breast cancer: Breast cancer is the most commonly cancer among women, with more than one million new cases identified worldwide each year [1]. An estimated 192,370 patients were newly diagnosed with breast cancer in the United States in 2009, and about 40,170 died of the disease [2]. Approximately 24% to 30% of women who have no lymph-node involvement at the time of diagnosis will relapse; the relapse rate for node-positive women is between 50%-60%[3]. The 5-year survival rates for those diagnosed with regional and metastatic disease are 80% and 26%, respectively[3]. Therefore, a safe and effective treatment remains a critical need.
Oncolytic virotherapy. Oncolytic virotherapy is a novel strategy using viruses, either naturally occurring or genetically modified, to selectively target and destroy tumor cells whilst leaving surrounding non-malignant cells unharmed[4]. The destruction of cancer cells occurs either through direct lytic rupture by multi-cycle viral replication or the subsequent induction of apoptosis[5] and successful application of virotherapy requires preferential and efficient amplification of the virus to lyse cancer cells. NS1 gene deficient RSV (ΔNS1 RSV) functions as an oncolytic virus against breast cancer.
RSV biology. RSV belongs to the family Paramyxoviridae, subfamily Pneumovirinae, genus Pneumovirus. The viral RNA is approximately 15 kb in size and is flanked by a leader region at the 3′ extremity of the genome and by a trailer region at the 5′ extremity (FIG. 1). The viral genome contains individual genes for ten viral proteins [6]. The NS1 gene, unique to members of the genus Pneumovirus [7], is promoter-proximally located at the 3′ end of the viral genome and its mRNA is the most abundant of the RSV transcripts in a linear start-stop-restart mode [8]. NS1 protein is referred to as nonstructural since it has not been detected in RSV particles. NS1 is exclusively found in RSV-infected cells. Our group, along with others, has found that NS1 can counter the type I IFN signaling during RSV infection [9, 10], implying that NS1 plays a direct role in inhibiting the host's innate immune response.
RSV can be rendered nonpathogenic by mutating the NS1 gene so that it no longer inhibits IFN release, which attenuates viral infection in normal cells. However, these nonpathogenic RSV, ΔNS1 RSV, are still oncolytic because tumor cells are defective in their ability to produce and respond to IFN and, therefore, efficiently support the propagation of ΔNS1 RSV.